Background
Phase 3, double-blind RCT; N=599; metastatic androgen pathway modulation–sensitive (castration-sensitive) prostate cancer harboring homologous recombination repair (HRR) gene alterations. Talazoparib is a PARP inhibitor; enzalutamide is an androgen-receptor inhibitor.
Results
Interventions and follow up: Arm A: Talazoparib 0.5 mg + enzalutamide 160 mg, oral once daily (n=300)
Arm B: Placebo + enzalutamide 160 mg, oral once daily (n=299)
Primary endpoint: Investigator-assessed radiographic PFS (rPFS)
Key secondary endpoint: OS
mFollow up: NR (~3 years planned)
Results: 3yr rPFS: 77% vs 56%; HR 0.48, 95% CI 0.36–0.65; P<.001
rPFS (BRCA-mutated subgroup): ~63% reduction in progression or death
3yr OS (interim): 78% vs 72%; HR 0.77, 95% CI 0.56–1.04 (immature)
Arm B: Placebo + enzalutamide 160 mg, oral once daily (n=299)
Primary endpoint: Investigator-assessed radiographic PFS (rPFS)
Key secondary endpoint: OS
mFollow up: NR (~3 years planned)
Results: 3yr rPFS: 77% vs 56%; HR 0.48, 95% CI 0.36–0.65; P<.001
rPFS (BRCA-mutated subgroup): ~63% reduction in progression or death
3yr OS (interim): 78% vs 72%; HR 0.77, 95% CI 0.56–1.04 (immature)
Adverse events
Hematologic: anemia 71.2% (grade ≥3 anemia 51%), neutropenia 27.1%
Constitutional: fatigue 28.4%
Serious AEs: 42% vs 32%
Discontinuation: ~20% (talazoparib arm); 2 treatment-related deaths
Constitutional: fatigue 28.4%
Serious AEs: 42% vs 32%
Discontinuation: ~20% (talazoparib arm); 2 treatment-related deaths
Conclusions
Adding talazoparib to enzalutamide reduced the risk of radiographic progression or death by 52% (HR 0.48) in HRR-altered metastatic hormone-sensitive prostate cancer, with the greatest benefit in BRCA-mutated tumors. OS is trending favorable but immature. Anemia is frequent and often requires dose modification.
Key Limitations
Benefit confined to the biomarker-selected HRR population; not generalizable to HRR-non-altered mHSPC. rPFS is a surrogate endpoint and OS remains immature. Substantial hematologic toxicity (grade ≥3 anemia 51%) with ~20% discontinuation; control was enzalutamide alone rather than an intensified doublet/triplet ADT backbone.
Clinical Context
Moves the PARP + androgen-receptor-inhibitor combination from castration-resistant disease (TALAPRO-2, FDA-approved for HRR-altered mCRPC) into the earlier hormone-sensitive setting, reinforcing upfront HRR testing. The mHSPC indication is not yet FDA-approved as of June 2026; results presented at the 2026 ASCO Annual Meeting.